Inflammation and postinfarct remodeling: Overexpression of IκB prevents ventricular dilation via increasing TIMP levels
TL;DR: Reducing NF-kappaB activity via IkappaB overexpression after MI positively influences ECM remodeling by reducing MMP-2 and -9 levels while increasing TIMP-1, -2, -3, and -4 levels.
Abstract: Objective: Nuclear factor-kappa B (NF-κB) orchestrates genes involved in inflammation and extracellular matrix (ECM) remodeling following myocardial infarction (MI). The objective of the present study was to investigate the effect of overexpression and mode of function of IκB, the natural inhibitor of NF-κB, on ECM remodeling in a rat model of MI.
Methods: MI was induced in male Sprague-Dawley rats by ligation of the left anterior descending coronary artery (LAD) and was followed by adenovirus-mediated intramyocardial transfection of IκB ( n =26) or LacZ reporter genes ( n =26). Sham-operated animals ( n =14) served as controls.
Results: In transthoracic echocardiography 49 days after MI, systolic and diastolic left ventricular dimensions were reduced while fractional shortening was preserved in the treatment group. Additionally, evaluation on the isolated heart showed an attenuated downward shift of pressure–volume relationships in the IκB group compared to LacZ. NF-κB p65 DNA binding activity was diminished both at 5 and 49 days post-MI in the treatment group. Five days post-MI in the treatment group, protein levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β were significantly reduced by 72.6% and 73.2%, respectively, compared to LacZ ( p <0.05). In parallel, matrix metalloproteinase (MMP)-2 and MMP-9 levels were reduced 5 days post-MI, with MMP-9 still being decreased 49 days post-MI ( p <0.01). In contrast, tissue inhibitors of metalloproteinases (TIMP)-1, -2, and -3 were increased compared to LacZ ( p <0.01 and p <0.05, respectively) 5 days post-MI. After 49 days, TIMP-2, -3, and -4 expressions were significantly elevated ( p <0.05).
Conclusion: Reducing NF-κB activity via IκB overexpression after MI positively influences ECM remodeling by reducing MMP-2 and -9 levels while increasing TIMP-1, -2, -3, and -4 levels. Therefore, IκB overexpression prevents ventricular dilation and consequently preserves cardiac function.
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TL;DR: It was observed that TGP could relieve myocardial remodeling in rats induced by abdominal aorta ligation and decrease the level of angiotensin II and I/III collagen ratio, pathogenic cytokines and inhibit the expression and activities of MMPs.
16 citations
TL;DR: Thyroid hormones modulates TLR4/NF-κβ expression in the infarcted hearts of rats and decreases xanthine oxidase expression, related to cardiac functional improvement after infarction.
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TL;DR: PGz improved survival and contractile performance, associated with improved myocardial remodeling, and may serve as a simple, safe, non-invasive therapeutic modality to improve myocardia function after MI.
Abstract: Myocardial infarction (MI) may produce significant inflammatory changes and adverse ventricular remodeling leading to heart failure and premature death. Pharmacologic, stem cell transplantation, and exercise have not halted the inexorable rise in the prevalence and great economic costs of heart failure despite extensive investigations of such treatments. New therapeutic modalities are needed. Whole Body Periodic Acceleration (pGz) is a non-invasive technology that increases pulsatile shear stress to the endothelium thereby producing several beneficial cardiovascular effects as demonstrated in animal models, normal humans and patients with heart disease. pGz upregulates endothelial derived nitric oxide synthase (eNOS) and its phosphorylation (p-eNOS) to improve myocardial function in models of myocardial stunning and preconditioning. Here we test whether pGz applied chronically after focal myocardial infarction in rats improves functional outcomes from MI. Focal MI was produced by left coronary artery ligation. One day after ligation animals were randomized to receive daily treatments of pGz for four weeks (MI-pGz) or serve as controls (MI-CONT), with an additional group as non-infarction controls (Sham). Echocardiograms and invasive pressure volume loop analysis were carried out. Infarct transmurality, myocardial fibrosis, and markers of inflammatory and anti-inflammatory cytokines were determined along with protein analysis of eNOS, p-eNOS and inducible nitric oxide synthase (iNOS).At four weeks, survival was 80% in MI-pGz vs 50% in MI-CONT (p< 0.01). Ejection fraction and fractional shortening and invasive pressure volume relation indices of afterload and contractility were significantly better in MI-pGz. The latter where associated with decreased infarct transmurality and decreased fibrosis along with increased eNOS, p-eNOS. Additionally, MI-pGz had significantly lower levels of iNOS, inflammatory cytokines (IL-6, TNF-α), and higher level of anti-inflammatory cytokine (IL-10). pGz improved survival and contractile performance, associated with improved myocardial remodeling. pGz may serve as a simple, safe, non-invasive therapeutic modality to improve myocardial function after MI.
15 citations
TL;DR: Reduced injury is due to a combination of adaptive metabolic reprogramming, improved cell survival, and decreased inflammatory cell recruitment, suggesting that ephrinA1-Fc enhances the capacity of the heart to withstand an ischemic insult.
Abstract: EphrinA1, a membrane-bound receptor tyrosine kinase ligand expressed in healthy cardiomyocytes, is lost in injured cells following myocardial infarction. Previously, we have reported that a single intramyocardial injection of chimeric ephrinA1-Fc at the time of ischemia reduced injury in the nonreperfused myocardium by 50% at 4 days post-MI by reducing apoptosis and inflammatory cell infiltration. In a clinically relevant model of acute ischemia (30min)/reperfusion (24hr or 4 days) injury, we now demonstrate that ephrinA1-Fc reduces infarct size by 46% and completely preserves cardiac function (ejection fraction, fractional shortening, and chamber dimensions) in the short-term (24hrs post-MI) as well as long-term (4 days). At 24 hours post-MI, diminished serum inflammatory cell chemoattractants in ephrinA1-Fc-treated mice reduces recruitment of neutrophils and leukocytes into the myocardium. Differences in relative expression levels of EphA-Rs are described in the context of their putative role in mediating cardioprotection. Validation by Western blotting of selected targets from mass spectrometry analyses of pooled samples of left ventricular tissue homogenates from mice that underwent 30min ischemia and 24hr of reperfusion (I/R) indicates that ephrinA1-Fc administration alters several regulators of signaling pathways that attenuate apoptosis, promote autophagy, and shift from FA metabolism in favor of increased glycolysis to optimize anaerobic ATP production. Taken together, reduced injury is due a combination of adaptive metabolic reprogramming, improved cell survival, and decreased inflammatory cell recruitment, suggesting that ephrinA1-Fc enhances the capacity of the heart to withstand an ischemic insult.
15 citations
Journal Article•
TL;DR: A novel strategy to treat abdominal aortic aneurysm by simultaneous inhibition of both NF-κB and ets by using chimeric decoy oligodeoxynucleotides (ODN).
Abstract: Background— Two phenomena, inflammation and matrix degradation, contribute to the progression of abdominal aortic aneurysm (AAA). Importantly, the inflammation is regulated by the transcription factor nuclear factor (NF)–κB, whereas the destruction and degradation of elastin fibers by matrix metalloproteinases (MMP) are regulated by ets. Thus, we developed a novel strategy to treat AAA by simultaneous inhibition of both NF-κB and ets by using chimeric decoy oligodeoxynucleotides (ODN). Methods and Results— AAA was induced in rats by transient aortic perfusion with elastase, whereas transfection of decoy ODN was performed by wrapping a delivery sheet containing decoy ODN around the aorta. Gel-mobility shift assay at 7 days after treatment demonstrated that both NF-κB and ets binding activity were simultaneously inhibited by chimeric decoy ODN. Transfection of chimeric decoy ODN resulted in significant inhibition of the progression of AAA such as aneurysmal dilation at 4 weeks after treatment as compared wi...
14 citations
References
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TL;DR: In this paper, a review of recent progress as well as unanswered questions regarding the regulation and function of NF-kappaB and IKK is presented, focusing on recent progress and unanswered questions.
3,342 citations
TL;DR: The extent of ventricular enlargement after infarction is related to the magnitude of the initial damage to the myocardium and, although an increase in cavity size tends to restore stroke volume despite a persistently depressed ejection fraction, ventricular dilation has been associated with a reduction in survival.
Abstract: An acute myocardial infarction, particularly one that is large and transmural, can produce alterations in the topography of both the infarcted and noninfarcted regions of the ventricle. This remodeling can importantly affect the function of the ventricle and the prognosis for survival. In the early period, infarct expansion has been recognized by echocardiography as a lengthening of the noncontractile region. The noninfarcted region also undergoes an important lengthening that is consistent with a secondary volume-overload hypertrophy and that can be progressive. The extent of ventricular enlargement after infarction is related to the magnitude of the initial damage to the myocardium and, although an increase in cavity size tends to restore stroke volume despite a persistently depressed ejection fraction, ventricular dilation has been associated with a reduction in survival. The process of ventricular enlargement can be influenced by three interdependent factors, that is, infarct size, infarct healing, and ventricular wall stresses. A most effective way to prevent or minimize the increase in ventricular size after infarction and the consequent adverse effect on prognosis is to limit the initial insult. Acute reperfusion therapy has been consistently shown to result in a reduction in ventricular volume. The reestablishment of blood flow to the infarcted region, even beyond the time frame for myocyte salvage, has beneficial effects in attenuating ventricular enlargement. The process of scarification can be interfered with during the acute infarct period by the administration of glucocorticosteroids and nonsteroidal antiinflammatory agents, which result in thinner infarcts and greater degrees of infarct expansion. Modification of distending or deforming forces can importantly influence ventricular enlargement. Even short-term augmentations in afterload have deleterious long-term effects on ventricular topography. Conversely, judicious use of nitroglycerin seems to be associated with an attenuation of infarct expansion and long-term improvement in clinical outcome. Long-term therapy with an angiotensin converting enzyme inhibitor can favorably alter the loading conditions on the left ventricle and reduce progressive ventricular enlargement as demonstrated in both experimental and clinical studies. With the former therapy, this attenuation of ventricular enlargement was associated with a prolongation in survival. The long-term clinical consequences of long-term angiotensin converting enzyme inhibitor therapy after myocardial infarction is currently being evaluated. Although studies directed at attenuating left ventricular remodeling after infarction are in the early stages, it does seem that this will be an important area in which future research might improve long-term outcome after infarction.
2,815 citations
"Inflammation and postinfarct remode..." refers background in this paper
...Experimental and clinical failure of different approaches blocking the inflammatory cascade in the first hours after the ischemic injury demonstrated the importance of inflammation for infarct stabilization and wound healing [25]....
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TL;DR: This review summarizes the current understanding of the cellular and molecular mechanisms regulating the inflammatory response following myocardial ischemia and reperfusion and concludes that by promoting more effective tissue repair, it may be possible to reduce the deleterious remodeling.
Abstract: One of the major therapeutic goals of modern cardiology is to design strategies aimed at minimizing myocardial necrosis and optimizing cardiac repair following myocardial infarction. However, a sound understanding of the biology is necessary before a specific intervention is pursued on a therapeutic basis. This review summarizes our current understanding of the cellular and molecular mechanisms regulating the inflammatory response following myocardial ischemia and reperfusion. Myocardial necrosis induces complement activation and free radical generation, triggering a cytokine cascade initiated by Tumor Necrosis Factor (TNF)-α release. If reperfusion of the infarcted area is initiated, it is attended by an intense inflammatory reaction. Interleukin (IL)-8 synthesis and C5a activation have a crucial role in recruiting neutrophils in the ischemic and reperfused myocardium. Neutrophil infiltration is regulated through a complex sequence of molecular steps involving the selectins and the integrins, which mediate leukocyte rolling and adhesion to the endothelium. Marginated neutrophils exert potent cytotoxic effects through the release of proteolytic enzymes and the adhesion with Intercellular Adhesion Molecule (ICAM)-1 expressing cardiomyocytes. Despite this potential injury, substantial evidence suggests that reperfusion enhances cardiac repair improving patient survival; this effect may be in part related to the inflammatory response. Monocyte Chemoattractant Protein (MCP)-1 is also markedly upregulated in the infarcted myocardium inducing recruitment of mononuclear cells in the injured areas. Monocyte-derived macrophages and mast cells may produce cytokines and growth factors necessary for fibroblast proliferation and neovascularization, leading to effective repair and scar formation. At this stage expression of inhibitory cytokines such as IL-10 may have a role in suppressing the acute inflammatory response and in regulating extracellular matrix metabolism. Fibroblasts in the healing scar undergo phenotypic changes expressing smooth muscle cell markers. Our previous review in this journal focused almost exclusively on reduction of the inflammatory injury. The current update is prompted by the potential therapeutic opportunity that the open vessel offers. By promoting more effective tissue repair, it may be possible to reduce the deleterious remodeling, that is the leading cause of heart failure and death. Elucidating the complex interactions and regulatory mechanisms responsible for cardiac repair may allow us to design effective inflammation-related interventions for the treatment of myocardial infarction.
1,966 citations
"Inflammation and postinfarct remode..." refers background in this paper
...Acute MI starts a cytokine cascade in both the infarcted and non-infarcted myocardium via complement activation and reactive oxygen species [1–3]....
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TL;DR: It is shown that the transcription factor NF-κB has been shown to be the target of several anti-inflammatory and anticancer drugs.
Abstract: Beginning with its discovery in 1986 and continuing through the present, the transcription factor NF-κB has attracted widespread interest based on its unusual regulation, the variety of stimuli that activate it, the diverse genes and biological responses that it controls, the striking evolutionary conservation of structure and function among family members, and its apparent involvement in a variety of human diseases (Table (Table1).1). Importantly, and consistent with the last point, NF-κB has been shown to be the target of several anti-inflammatory and anticancer drugs.
988 citations
TL;DR: The extent of ventricular enlargement after infarction is related to the magnitude of the initial damage to the myocardium and, although an increase in cavity size tends to restore stroke volume despite a persistently depressed ejection fraction, ventricular dilation has been associated with a reduction in survival.
Abstract: Acute transmural myocardial infarction initiates a series of changes in left ventricular (LV) volume, regional function and geometry. This process, known as postinfarction LV remodeling, may continue for months or years following the initial ischemic event. To characterize the components of late ventricular remodeling, biplane left ventriculography was performed in 52 patients at 3 weeks and repeated at 1 year after first anterior myocardial infarction. Biplane circumference and contractile and noncontractile segment lengths were measured. Global geometry was evaluated by calculating a sphericity index and regional geometry was assessed by measurement of endocardial curvature. End-diastolic (ED) volume was increased at 3 weeks and enlarged further at one year. This late enlargement was accompanied by an increase in the length of the contractile segment and an increase in sphericity, whereas the length of the noncontractile segment decreased. Curvature analysis revealed that this late increase in sphericity resulted from flattening of regions of presumably high tension negative curvature at the infarct border zone and from less bulging of the infarcted anterior wall. Even in patients selected for late ventricular enlargement (change in ED volume > 20 ml, n = 19), this increase in volume resulted from both lengthening of the contractile segment and an increase in sphericity without a change in the noncontractile segment length. Thus, late ventricular enlargement after anterior myocardial infarction results from an increase in contractile segment length and a change in ventricular geometry and is not a result of progressive infarct expansion.
935 citations